25-Hydroxyvitamin D and Total Cancer Incidence and Mortality: A Meta-Analysis of Prospective Cohort Studies

Abstract

Epidemiological studies have suggested inconclusive associations between 25-hydroxyvitamin D and total cancer incidence and mortality. The aim of this study was to quantitatively assess these associations by combining results from prospective cohort studies. A systematic literature search was implemented in PubMed and Scopus databases in April 2019. Comparing the highest with the lowest categories, the multivariate-adjusted relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were pooled using a random-effects model. A trend estimation was performed using a two-stage, dose-response, meta-analysis method. Twenty-three independent prospective studies were included for data synthesis. Eight studies investigated the association between 25-hydroxyvitamin D and the risk of cancer incidence (7511 events and 70,018 participants), and the summary estimate showed that 25-hydroxyvitamin D is marginally associated with cancer risk (Summary RR = 0.86; 95% CI: 0.73, 1.02; I2 = 70.8%; p = 0.001). Sixteen studies investigated the association between 25-hydroxyvitamin D and the risk of cancer mortality (8729 events and 101,794 participants), and a higher 25-hydroxyvitamin D concentration was inversely associated with the risk of cancer mortality (Summary RR = 0.81; 95% CI: 0.71, 0.93; I2 = 48.8%, p = 0.012). Dose-response analysis indicated that the risk of cancer incidence was reduced by 7% (RRs = 0.93; 95% CI: 0.91, 0.96), and the risk of cancer mortality was reduced by 2% (RRs = 0.98; 95% CI: 0.97, 0.99), with each 20 nmol/L increment of 25-hydroxyvitamin D concentration. This meta-analysis provides evidence that a higher 25-hydroxyvitamin D concentration is associated with a lower cancer incidence and cancer mortality.

Effect of Vitamin D Supplementation on Survival of Digestive Tract Cancer Patients with Low Bioavailable 25-Hydroxyvitamin D Levels: A Post Hoc Analysis of the AMATERASU Randomized Clinical Trial

“…In this post hoc analysis of the AMATERASU trial, daily supplementation with 2000 IU of vitamin D significantly improved 5 year RFS in the subgroup of patients with low bioavailable 25(OH)D levels, but not in the subgroup with high bioavailable 25(OH)D levels. In our previous analysis of the AMATERASU trial, vitamin D was not effective in the subgroup of patients with low serum levels (<20 ng/mL) of total 25(OH)D at baseline, contrary to our expectation that vitamin D would be effective only in the subgroup with low total 25(OH)D [4]. However, in this post hoc study, we demonstrated that vitamin D supplementation may be effective only in cancer patients with low bioavailable 25(OH)D levels.…”

“…This study was a post hoc analysis of the AMATERASU trial conducted in Japan. Details of the study have been previously reported [4]. Briefly, 417 patients with digestive tract cancer from the esophagus to the rectum participated in a randomized, double-blind, clinical trial to compare the effects of vitamin D3 supplements (2000 IU/day) and placebo on RFS and OS at an allocation ratio of 3:2, at the International University of Health and Welfare Hospital (Ohtawara, Tochigi prefecture, Japan) between January 2010 and February 2018.…”

“…In addition to this classical pathway, the 25(OH)D molecule in the serum has been hypothesized to be absorbed by cancer cells, to be activated by 1α−hydroxylase and bind to vitamin D nuclear receptors within the cell, to inhibit aberrant cellular proliferation by regulating a variety of genes, and to prevent cancer relapse [3]. A meta-analysis of 16 prospective cohort studies including more than 100,000 patients showed that higher total 25(OH)D levels in serum were significantly associated with decreased cancer-specific mortality [4] independent of cancer site or pathological subtype. However, contrary to expectations, recent randomized clinical trials (RCTs) have demonstrated that vitamin D supplementation, compared with placebo, did not result in significant improvement of relapse or progression-free survival among the total study population or a subgroup of patients with low total 25(OH)D levels (<20 ng/mL) in digestive tract cancer [5] and advanced or metastatic colorectal cancer [6].…”

Vitamin D and Clinical Cancer Outcomes: A Review of Meta‐Analyses

“…With total cancer incidence as the outcome, one of these meta-analyses combined data from 8 prospective cohort studies (70,018 participants and 7511 events) (13). The summary relative risk (RR) estimate of the highest 25(OH)D category compared to the lowest was 0.86 (95% confidence interval (CI): 0.73-1.02), indicating a marginal relationship in the inverse direction, with a significant between-study heterogeneity (I 2 =70.8%).…”

“…A recent meta-analysis had total cancer mortality as the outcome (13). This report combined data from 16 prospective cohort studies on 101,794 participants without cancer at baseline, 8729 of whom had a cancer-related death.…”